Review
Figueira AnaCristina Corrêa et al. Efficacy of Exercise on …  Int
Efficacy of Exercise on Breast Cancer Outcomes: A Systematic
Review and Meta-analysis of Preclinical Data
Authors
Ana Cristina Corrêa Figueira1, 2, António Cortinhas3, Jorge Pinto Soares3, 4, José Carlos Leitão3, 4, Rita Pinho Ferreira5,
Jose Alberto Duarte1
Affiliations
1 CIAFEL, Research Center in Physical Activity, Health and
Leisure, Faculty of Sport, University of Porto, Porto,
Portugal
2 Department of Sciences and Technologies/Sport Sciences,
Polytechnic Institute of Setúbal, Setúbal, Portugal
3 Department of Sport Sciences Exercise and Health,
University of Trás-os-Montes and Alto Douro, Vila Real,
Portugal
4 CIDESD, Research Center in Sports, Health Sciences and
Human, Portugal
5 QOPNA, Department of Chemistry, University of Aveiro,
Aveiro, Portugal
Key words
tumor burden, tumor microenvironment, proliferation,
apoptosis, angiogenesis, effect size
accepted 08.01.2018
Bibliography
DOI  https://doi.org/10.1055/s-0044-101149
Published online: 2018
Int J Sports Med
© Georg Thieme Verlag KG Stuttgart · New York
ISSN 0172-4622
Correspondence
Dr. Ana Cristina Corrêa Figueira, MS
Polytechnic Institute of Setúbal
Setúbal, Portugal
Department of Sciences and Technologies/Sport Sciences
Campus IPS, Estefanilha
Introduction
Breast cancer is one of the most commonly diagnosed malignancies
among women, and it is the leading cause of death by cancer in
women in several countries. As a result, breast cancer is also an in-
creasingly common field of study [16]. In recent years, researchers
in the field of exercise oncology have begun to investigate the asso-
ciation between active behaviors and cancer, as well as the cellular
and molecular mechanisms underlying that association [43, 52].
Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
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Setúbal, 2914-504
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Tel.:  + 351/968/048 821, Fax:  + 351/265/710 891
ana.figueira@ese.ips.pt
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Abs trac t
The use of preclinical models to investigate antitumor effects
of exercise on breast tumor (BT) development and progression
are critical. However, published results have not been quanti-
tatively summarized or examined for potential exercise-mod-
erating variables. We conducted this review to summarize and
quantify the effect-size of exercise on BT outcomes in preclini-
cal studies. A literature search was performed in MEDLINE,
PubMed, Web of Science and System for Information on Grey
Literature in Europe (SIGLE) databases. Risk of bias was assessed
using SYRCLE’s RoB tool. A total of 116 correlations were per-
formed to analyze 28 preclinical studies published through
December 2016, which included 2,085 animals and 51 exercise
programs. Positive effects of small, medium and large magni-
tude were observed in tumor incidence, growth and multiplic-
ity, respectively. In the tumor microenvironment, positive ef-
fects of large magnitude were also observed in proliferation
and apoptosis but not in angiogenesis. Moderator variables
correlated with higher intervention effects were identified
along with a considerable heterogeneity in exercise protocols
that precluded us from clearly perceiving the benefits of exer-
cise exposure. In conclusion, exercise performed under spe-
cific conditions benefits BT outcomes. Preclinical studies with
exercise designs mimicking exercise exposure that can be used
in clinical contexts are needed.
The beneficial effects of regular physical activity and structured
exercise training (considered here to be exercise) on breast cancer
prevention and sur vivorship are now widely recognized
[11, 17, 18, 20, 41]. Furthermore, although a few aspects of the
beneficial association between exercise and tumor outcomes re-
main uncertain, being active is highly recommended during and
after cancer treatment [3, 4, 57]. Exercise is important to control
and reduce the side effects of cancer therapy [10, 36, 38, 56, 58, 59],
 Review
and being active during and after treatment appears to reduce
mortality among women [26, 29, 30, 48].
Published studies have sought to confirm a link between exer-
cise and biological changes that promote better tumor outcomes
possibly achieved via the modulation of tumor behavior [49]. In-
deed, knowledge of cell proliferation, the cellular apoptosis rate
and proangiogenic and antiangiogenic events are important for
predicting the behavior of tumors and their metastatic potential,
and there is evidence that exercise may exert a beneficial effect by
altering these processes [13, 45, 54].
The current literature suggests that exercise, when performed
at a moderate to vigorous intensity for 75–150 min per week, is
safe and well tolerated by patients during and after therapy [35, 57].
However, the majority of investigations focusing on humans have
ascertained an appropriate activity level using subjective (i. e., self-
reported) measures, which obscure knowledge about the type, in-
tensity, duration and frequency of exercise that confers optimal
benefits [19].
Research on the topic using animal models to mimic the disease
in humans is essential to reveal the biological mechanisms by which
exercise exerts its beneficial effects, identify the amounts of exer-
cise that yield better outcomes and provide information about
tumor physiology [64]. However, the results of preclinical research
are still heterogeneous, likely due to the diversity of exercise ex-
perimental protocols that preclude a clear understanding of the
strength of exercise effects, as well as the type, duration, intensity
and frequency of exercise that most effectively prevent and con-
trol breast cancer in animals [63].
Although several reviews addressing the effects of exercise on
breast cancer in animal models have been conducted, the results
of such reviews have not been assessed quantitatively; no meta-
analytic procedures were used to report effect sizes or to scrutinize
potential moderators of intervention effects.
Our study addressed this substantial gap in the literature by
quantifying the effects of exercise on breast cancer outcomes in
animals. This meta-analysis focuses primarily on the effect size of
exercise on tumor outcomes as assessed by changes in incidence
(i. e., the total of tumors per group of animals, active vs. sedentary),
multiplicity (i. e., the number of tumors per animal, active vs. sed-
entary), tumor weight, tumor volume and changes in the tumoral
microenvironment (i. e., markers of cellular proliferation and ap-
optosis and markers of angiogenesis). This quantitative assessment
also examines features of exercise designs that influence the exer-
cise-cancer relation in different ways, by analyzing which ones are
associated with better intervention effects.
Methods
This meta-analysis was conducted according to the Preferred Re-
porting Items for Systematic Reviews and Meta-Analyses statement
[50]. This article does not contain any studies with human partici-
pants or animals [24].
Search strategy
A literature search, conducted once in April 2016 and again in De-
cember 2016, was performed on the following databases: MED-
Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
Thieme
LINE, PubMed, Web of Science (Web of Science; Current Contents
Connect), and System for Information on Grey Literature in Europe
(SIGLE), and in the search we used MeSH terms and keywords re-
lated to breast cancer, exercise and animals [Electronic supplemen-
tary material (ESM) Table S1]. Booleans were also used, when pos-
sible, to form search expressions combining the MeSH terms (ESM
Fig. S1). We also conducted an additional manual search of the ref-
erences in the manuscripts retrieved.
Inclusion criteria
We included studies, if they satisfied the following criteria: (1) they
were performed on animals and written in English; (2) they com-
pared the effects of an active and a sedentary lifestyle on tumor
outcomes; (3) they investigated the effects of exercise following
tumor induction. We excluded studies, if: (1) they addressed the
cancer-preventive effects of exercise; (2) they endeavored to de-
termine the acute effects of exercise; (3) they combined exercise
exposure with chemical therapy exposure; (4) they described data
that made it impossible to calculate effect sizes.
Downloaded by: York University libraries. Copyrighted material.
Two sources were excluded because full-text versions were un-
available for purchase and could not be obtained; the authors of
those sources were contacted and the manuscripts requested, but
no response was received.
Data collection process
Three authors (ACCF, RF and JAD) independently assessed the eli-
gibility of the studies and graded their methodological quality
using the SYstematic Review Centre for Laboratory animal Experi-
mentation (SYRCLE)’s Risk of Bias (RoB) tool (Cochrane RoB tool
adapted for animals). This quality assessment tool rates the stud-
ies’ procedures as “high.” “unclear” or “low” risk of bias in six di-
mensions (selection, performance, detection, attrition, reporting
and other bias), adapted for aspects of bias that play a specific role
in animal studies (ESM Fig. S2) [28, 74]. Any disagreements were
resolved by consensus or by involving a fourth reviewer (JPS). Three
reviewers (ACCF, AC, JCL) extracted and interpreted the data and,
when necessary, contacted the authors to request additional infor-
mation.
The following information was extracted from each manuscript:
name of the first author, year of publication, sample size and type
of animal(s) used, as well as tumor induction protocol, tumor out-
come data and exercise design features.
Statistical analysis
We performed the statistical analysis using Comprehensive Meta-
Analysis (CMA) software version 2.2.057 (Biostat Inc, Englewood,
New Jersey, USA).
To estimate the effect size of the exercise-cancer relation, we
used the correlation coefficient r when available. When r was una-
vailable, we used averages, standard deviations and percentages
and converted these statistics into r values. In comparative stud-
ies, we converted to r values using exact p values [55]. Considering
the different methodologies adopted in each study a random-­
effects model was used and Cohen’s (1988) criteria for small
(r = 0.10), medium (r = 0.30) and large (r = 0.50) effects were con-
sidered to quantify the magnitude of the results [6].
▶Table 1 Codification of moderators.

Moderator Values Coding Description

Exercise type
Exercise intensity
Distance covered
Exercise duration
Exercise frequency
0 = Treadmill; 1 = Free-wheel;
2 = Motorized-wheel
0 = ND; 1 = Low; 2 = Moderate;
3 = Vigorous
0 = NR; 1 = Short distance; 2 = Long
distance
0 = NR; 1 = Short duration;
2 = Medium duration; 3 = Long
duration; 4 = Very long Duration
0 = 5 d/week; 1 = 6 d/week; 2 = 7 d/
week
Type of exercise performed. Protocols in treadmill were considered as forced exercise.
For voluntary exercise, protocols in free-wheel or in motorized-wheel were considered.
0: Not defined; 1: Until 50 % of maximum speed; 2: 50 %-70 % of maximum speed; 3:
Above 70 % of maximum speed.
Distance covered during the entire program 0: Not registered; 1: Group of animals
who covered shorter distances; 2: Group of animals who covered longer distances.
Daily exercise duration. 0: Not registered; 1: Under 30 min; 2: Between 30 and 45 min;
3: Between 46 and 60 min; 4: Above 60 min.
Weekly frequency. In voluntary exercise protocols, if frequency was not defined by the
authors, a frequency of 7 days is always assumed.

Heterogeneity and risk of bias
We used Cochran’s Q and I2 tests to gauge heterogeneity and per-
formed a sensitivity analysis omitting one study at a time from the
initial meta-analysis. We also scrutinized potential moderators of
intervention effects (e. g. voluntary or forced exercise, intensity,
Twenty studies analyzed tumor incidence [7–9, 14, 21, 33, 34, 42,
46, 47, 51, 66–69, 72, 73, 75–77], and five of those studies (25 %)
reported adverse effects of exercise [9, 21, 46, 66, 73]. Of the 14
studies that analyzed tumor multiplicity [8, 9, 14, 23, 33, 34, 46,
47, 53, 60, 69, 75–77], two (14.3 %) reported negative data associ-

Downloaded by: York University libraries. Copyrighted material.

distance covered, duration and frequency) selected based on the- ated with exercise [9, 60]. Tumor weight was observed in nine stud-
ory and prior findings [64]. We then accordingly coded interven- ies [2, 14, 33, 34, 60, 72, 73, 76, 77], and tumor volume was ob-
tion features (▶Table 1). served in 11 studies [2, 7, 9, 14, 23, 31, 46, 53, 60, 70, 72]. Negative
To test for bias, we examined funnel plots and used Egger’s re- effects of exercise were reported by one study in tumor weight
gression and Begg’s rank correlation. (11.1 %) [14] and by three studies in tumor volume (27.3 %)
[7, 14, 46].
The tumor microenvironment was analyzed in only six studies
Results [15, 31, 33, 34, 39, 75], and negative data were reported in two
studies, but only in tumor angiogenesis [15, 39].
Study characteristics
As shown in ▶Fig. 1, we identified 271 articles in the above-men- Risk of bias and quality evidence
tioned databases plus 90 in searches of grey literature. After an We analyzed the proportion of “low”, “unclear” or “high” risk of
­initial analysis, fifty-one articles remained and were examined in bias, among studies, for each item in the tool [25]. In 89.29 %
detail; however, only 28 of the articles [2, 7–9, 14, 15, 21, 23, 31, 33, (n = 25) of the studies the randomization, the baseline character-
34, 39, 42, 46, 47, 51, 53, 60, 66–70, 72, 73, 75–77] fulfilled all of istics and the allocation concealment were adequate. The housing
the inclusion criteria. conditions were similar between groups in 85.71 % of the cases
Descriptive data regarding the selected studies are presented (n = 24), and in 96.43 % (n = 27) of the studies all the animals were
in ▶ Table 2. used in reported outcomes. The outcomes were completely re-
In total, we evaluated 51 programs, 18 of which used voluntary ported in 71.43 % (n = 20) of the cases. High risk of bias (64.29 %,
exercise (51.0 %), 11 used a free wheel (27.4 %) [7–9, 23, 39, 47,  n = 18) was observed in the “detection bias” dimension, mainly
60, 69, 70, 75, 76] and 7 a motorized wheel (21.5 %) [33, 34, 42, 47,  due to the unreported conditions in which the animals of the
51, 69, 77]. Forced exercise on a treadmill was used in 13 studies ­different experimental groups were sacrificed. Individually, only
(49.0 %) [2, 9, 14, 15, 21, 31, 46, 53, 66–68, 72, 73]. one study [51] was rated with high (66.67 %) and unclear (22.22 %)
Exercise intensity was measured in 33 protocols (64.7 %). Mod- risk of bias. The remaining studies were rated with low risk of bias
erate-intensity exercise was the most frequently used (45.5 %), fol- (ESM Table S3).
lowed by low-intensity exercise (30.3 %) and vigorous-intensity ex-
ercise (24.2 %). Only 54.4 % of the experimental protocols have de- Effect size of exercise on tumor outcomes
fined exercise bout durations (very long: 3.5 %; long: 25.0 %; After meta-analytic procedures the results showed that exercise
medium: 53.6 %; short: 17.9 %). significantly reduces tumor burden in animals. We performed a
The duration of the experiments varied from 2 to 35 weeks, and total of 116 correlations, 37 for incidence (▶ Fig. 2a), 20 for multi-
27 of these lasted more than one month [2, 7–9, 14, 15, 21, 23,  plicity (▶ Fig. 2b), 14 for tumor weight (▶ Fig. 2c) and 15 for vol-
31, 33, 34, 39, 42, 46, 47, 51, 53, 60, 66–70, 72, 75–77], with 17 ume (▶Fig. 2d), and relevant correlations were noted. Regarding
lasting more than two months [7–9, 14, 15, 21, 23, 33, 42, 46,  tumor microenvironment, ten correlations were made for prolif-
51, 53, 60, 66–68, 77]. eration (▶Fig. 3a), ten for angiogenesis (▶Fig. 3b) and 12 for ap-
Chemical models for breast cancer were the most frequently optosis (▶ Fig. 3c). We also found significant and positive results
used (67.86 %) [7, 8, 14, 15, 21, 33, 34, 42, 46, 47, 51, 66– in proliferation and apoptosis but not in angiogenesis.
69, 72, 75–77], followed by transgenic models (14.29 %) The positive impact of exercise was noted in incidence with a
[9, 23, 53, 60]. small magnitude (r = −0.202, p = 0.000; 95 % CI = −0.295; −0.106;

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
 Review Thieme

Reports after database Reports after manual

Identification

Grey literature search

searching searching
(n=90)
(n=271) (n=3)

Identified after duplicates

removed
(n=138)

Excluded after a first selection Remaining after a first

(n=65) selection (n=73)
Screening

Excluded after reading

abstracts (n=25)

Articles excluded (n=20)

Downloaded by: York University libraries. Copyrighted material.

Eligibility

Remaining for review

Studies:
(n=48)
• reporting prevention effects of exercise (n=6),
• reporting acute effects of exercise (n=2),
• reporting the normal mammary gland (n=2),
• with combined exposures (n=4),
• with data unsuitable for calculate effect size
(n=3),
Included

• with no data in analyzed variables (n=1).

Manuscripts included
(n=28)

Note: In some cases, exclusions were made due to the impossibility of calculating effect sizes from the
described data. The authors of such literature were contacted and additional statistics requested.

▶Fig. 1 Flowchart depicting the selection of studies for meta-analysis.

n = 1,871; k = 37), and with a large magnitude in multiplicity Sensitivity analysis

(r = −0.632, p = 0.000; 95 % CI = −0.766; −0.446; n = 1,034; k = 20).
Medium-level benefits were observed in tumor weight (r = −0.366,
p = 0.002; 95 % CI = −0.557; −0.139; n = 639; k = 14) and tumor vol-
ume (r = −0.443, p = 0.005; 95 % CI = −0.668; −0.143; n = 508; k = 15).
Significant large-magnitude benefits were observed in tumor
proliferation (r = −0.794, p = 0.000; 95 % CI = −0.881; −0.655;
n = 280; k = 10) and apoptosis (r = −0.798, p = 0.000; 95 %
CI = −0.872; −0.690; n = 264; k = 12). In tumor angiogenesis
(r = −0.256, p = 0.448; 95 % CI = −0.734;0.392; n = 110; k = 10), small
positive benefits were observed, but they were not statistically sig-
nificant.
We n ot i ce d s ig n i f i c a n t h ete r o g e n e i t y i n i n c i d e n ce
[Q(36) = 82.696, p = 0.000 (I2 = 57 %)], multiplicity [Q(20) = 530.844,
p = 0.000 (I2 = 96 %)], tumor weight [Q(13) = 191.797, p = 0.000
(I2 = 93 %)], tumor volume [Q(14) = 284.087, p = 0.000 (I2 = 95 %)],
proliferation [Q(9) = 51.840, p = 0.000 (I 2  = 83 %)], apoptosis
[Q(11) = 53.059, p = 0.000 (I 2  = 79 %)] and angiogenesis
[Q(7) = 154.379, p = 0.000 (I2 = 96 %)].
For incidence, removing the study judge at high risk of bias did not
reveal different results (r = −0.193, p = 0.000; 95 % CI = −0.285;
−0.097) in exercise effects (ESM Fig. S2a). Moreover, in the remain-
ing variables, removing one study at a time for the analysis did not
substantially alter our results (ESM Fig. S2b, c, d and S3a, b, c).
Moderator variables analysis
Because substantial variability in effect sizes can relate to exercise
features, we also analyzed moderator variables. Moderation in-
duced by exercise features was observed in the majority of the var-
iables that we analyzed (▶Table 3).
Voluntary exercise and forced exercise
The type of exercise performed is a moderating variable of exercise
effects that acts on tumor burden by decreasing it. In fact, tumor
burden exhibited benefits irrespective of whether the type of ex-

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
 ▶Table 2 List of all the publication used with the moderator variables considered for analysis and the main tumor outcomes.

Study [Reference] Animal/BC model Exercise design Tumor outcomes

n Study Type Intensity Distance Duration Frequency
duration covered
Moore et al, 1973 Sprague-Dawley rats 10 Ex + 11 19 wks MW – 466.288 Km 30 min/d 7 days/wk - ↓ Incidence in the active animals.
[51] (50 days old) Sed
DMBA (1.2 mg per
animal) Intravenous
administration
Cohen et al, 1988 F344 rats (50 days old) 30 Ex + 36 20 wks FW – 411 260 km – 7 days/wk - ↓ Incidence in the active animals;
[7] MNU (37.5 mg/Kg) i.p. Sed - ↑ Tumor volume in the active animals.
Thompson et al, Sprague-Dawley rats 35 Ex + 28 18wks TRDM Moderate – 15 min/d 5 days/wk - ↑ Incidence in the active animals.
1988 [66] (50 days old) Sed
DMBA (5 mg per
animal) g.i.
Lane et al, 1991 [42] BALB/c mice (42 days 33 Ex + 32 34 wks TRDM Low – 60 min/d 5 days/wk - ↓ Incidence in all the active animals under
old) Sed standard, restricted, and high fat diets.
DMBA (1 mg per 38 Ex + 48
animal during 6 wks) Sed
g.i. 31 Ex + 29
Sed
Cohen et al, 1993 Sprague-Dawley rats 30 Ex + 30 19 wks FW – – – 7 days/wk - ↓ Incidence in the active animals under low and
[8] (50 days old) Sed high fat diets;
DMBA (10 mg per

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
animal)
DMBA (5 mg per 30 Ex + 30 11 wks – – – - ↓ Multiplicity in the active animals under low and
animal) Sed high fat diets.
g.i.
Woods et al, 1994 C3H/HEN mice (52 31 Ex + 27 2 wks TRDM Moderate – 30 min/d 7 days/wk - ↑ Incidence in the active animals in both
[73] days old) subcutane- Ex  +  30 Vigorous – 125 min/d intensities;
ously inoculated Sed - ↓ Tumor weight in the active animals in both
(SCA-1) intensities.
Welsch et al, 1995 Sprague-Dawley rats 27 Ex + 27 5 wks FW – 4.344 to – 7 days/wk - ↓ Tumor volume in the active animals more
[70] (60 days old) Ex  +  27 7.562 km/ pronounced in long distance runners.
Transplantation of Sed day
MDA-MB231 human  > 7.562 km/
BC day
Thompson et al, F-344 rats 30 Ex + 30 12 wks TRDM Low – 20 min/d 5 days/wk - ↓ Incidence in all the active animals;
1995 [67] (50/57 days old) Ex Moderate – 40 min/d - ↓ Incidence even lower in the active animals
MNU (50 mg/Kg) i.p. 29 Ex + 29 20 min/d under low intensities and exercise bouts of medium
Ex  +  28 40 min/d duration; and under moderate intensities and
Sed exercise bouts of short duration.

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 of all the publication used with the moderator variables considered for analysis and the main tumor outcomes.
Continued.
▶Table 2 List

Study [Reference] Animal/BC model Exercise design Tumor outcomes

Review

n Study Type Intensity Distance Duration Frequency

duration covered
Thompson et al, F344 rats (50/57 days 30 Ex + 29 26 wks TRDM Low – 40 min/d 5 days/wk - ↓ Incidence in the active animals in all intensities.
1995 (1) [68] old) Ex + 28 Moderate –
MNU (37.5 mg/Kg) i.p. Ex + 30 Sed Vigorous –
Gillette et al, 1997 F-344 rats (50/57 days 32 Ex + 30 20.5 wks TRDM Moderate – 30 min/d 5 days/wk - ↑ Incidence in the active animals under standard
[21] old) Sed and restricted diets.
MNU (50 mg/Kg) i.p. 32 EX + 30
Sed
Westerlind et al, MNU (50 mg/Kg) i.p. 44 Ex + 40 2/4/6/8wks TRDM Moderate – 30 min/d 5 days/wk - = Tumor incidence in the active animals;
2003 [72] Sprague-Dawley rats Sed - ↓ Tumor weight in the active animals;
(21 days old) - ↓Tumor volume in the active animals.
MNU (50 mg/Kg)
MNU (25 mg/Kg) i.p. 79 Ex + 80 2/4/6/8wks TRDM Moderate – 30 min/d 5 days/wk - ↓ Incidence in the active animals;
Sed - ↓ Tumor weight in the active animals;
- ↓Tumor volume in the active animals.
Zhu et al, 2008 [76] Sprague-Dawley rats 52 Ex + 52 8 wks FW – 428.400 Km – 7 days/wk - ↓ Incidence in the active animals;
(21 days old) Sed - ↓ Multiplicity in the active animals;
MNU (50 mg/Kg) i.p. - ↓ Tumor weight in the active animals.
Zhu et al, 2009 [75] Sprague-Dawley rats 27 Ex + 27 8 wks FW – – – 7 days/wk - ↓ Incidence in the active animals;
(21 days old) Sed - ↓ Number of tumors in the active animals;
MNU (50 mg/Kg) i.p. - ↓ VEGF in the active animals;
- ↑ BAX, Caspase 3 and Apaf-1 in the active
animals;
- ↓ XIAP and BCL-2 in the active animals;
- ↓ p21cip1, Cyclin D1 and E2F-1 in the active
animals.
Jiang et al, 2009 Sprague-Dawley rats 45 Ex + 45 6 wks MW Low 299.250 Km – 7 days/wk - ↓ Incidence in the active animals;
[34] (21 days old) Sed - ↓ Multiplicity in the active animals;
MNU (50 mg/Kg) i.p. - ↓ Tumor weight in the active animals;
- ↑ BAX, Caspase 3 and Apaf-1 in the active
animals;
- ↓ BCL-2 and XIAP in the active animals;
- ↑ p27kip and p21cip1; ↓ Cyclin D1 and E2F-1, in
the active animals.
Colbert et al, 2009 MMTV-Wnt-1 20 Ex + 21 24 wks TRDM Moderate – 45 min/d 5 days/wk - ↑ Incidence in active animals in both intensities.
[9] Transgenic mouse Ex + 22 Sed 21 wks Vigorous –
(p53 + / − )
20 Ex + 21 23 wks FW – 430.500 Km – 7 days/wk - ↑ Multiplicity in the active animals;
Sed - ↓ Tumor volume in TRDM animals.
Jones et al, 2010 Athymic mice 25 Ex + 25 6 wk FW – 168/252 – 7 days/wk - ↑ Perfused vessels in the active animals;
[39] Orthotopically injected Sed Km - ↓ VEGF in the active animals;
Thieme

cells (MDA-MB-231) - ↑ CD31 in the active animals.

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
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 of all the publication used with the moderator variables considered for analysis and the main tumor outcomes.
Continued.
▶Table 2 List

Study [Reference] Animal/BC model Exercise design Tumor outcomes

n Study Type Intensity Distance Duration Frequency
duration covered
Mann et al, 2010 Sprague-Dawley rats 27 Ex 8 wks MW Vigorous 459.900 Km – 7 days/wk - ↓ Incidence in the active animals more pro-
[47] MNU (50 mg/Kg) i.p. 23 Ex FW – – – nounced under motorized wheel exercise;
 +  - ↓ Multiplicity in the active animals more
50 Sed pronounced under motorized wheel exercise.
Thompson et al, Sprague-Dawley rats 22 Ex + 33 8 wks MW Vigorous – – 7 days/wk - ↓ Incidence in the active animals;
2010 [69] MNU (50 mg/Kg) i.p. Ex + 55 Sed FW – 391.000 Km – - ↓ Multiplicity in the active animals.
Murphy et al, 2011 C3(1) Transgenic 12 Ex + 14 20 wks TRDM Moderate – 60 min/d 6 days/wk - ↓ Multiplicity in the active animals;
[53] mouse model of breast Sed - ↓ Tumor volume in the active animals.
tumor
Zhu et al, 2012 [77] Sprague Dawley rats 30 Ex + 30 10 wks MW Low 125.000 Km – 7 days/wk - ↓ Incidence in active the animals in both
(21 days old) Ex + 30 Sed MW Vigorous 245.000 Km – intensities;
MNU (50 mg/Kg) i.p. - ↓ Multiplicity in the active animals in both
intensities;
- ↓ Tumor weight in the active animals.
Goh et al, 2013 [23] PyMT Transgenic 13 Ex + 12 10 wks FW –  < 150 – 7 days/wk - ↓ Multiplicity in the active animals;
mouse of invasive Sed Km/ > 150 - ↓ Tumor volume in the active animals more
breast cancer km pronounced in long distance runners.
Steiner et al, 2013 C3(1)/SV40 Tag 12 Ex + 15 20 wks FW – – – 7 days/wk - ↑ Multiplicity in the active animals
[60] Transgenic mouse Sed - ↓ Tumor weight in the active animals

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
model of breast tumor - ↓ Tumor volume in active animals
Jiang et al, 2013 Sprague-Dawley rats 30 Ex + 30 10 wks MW Moderate 245.000 Km – 7 days/wk - ↓ Incidence in the active animals in both
[33] (21 days old) Ex  + 30 Vigorous 125.000 Km – intensities;
MNU (50 mg/Kg) i.p. Sed - ↓ Multiplicity in the active animals in both
intensities;
- ↓ Tumor weight in the active animals;
- ↑ BAX, ↓ BCL-2 in the active animals;
- ↑ p27 ↓ Cyclin D1 in the active animals.
Malicka et al, 2015 Sprague-Dawley rats 12 Ex + 10 12 wks TRDM Low – 28 min/d 5 days/wk - ↑ Incidence in the active animals under low
[46] (42 days old) Ex + 7 Moderate – 35 min/d intensity;
MNU (180 mg/Kg) i.p. Ex + 14 Sed Vigorous – 42 min/d - ↓ Incidence in the active animals under moderate
and vigorous intensities;
- ↓ Multiplicity in the active animals in all
intensities;
- ↓ Tumor volume in the active animals under
moderate and vigorous intensities;
- ↑ Tumor volume in the active animals under low
intensity.
Aveseh et al, 2015 BALB/c mice (35 days 10 Ex + 10 7 wks TRDM Moderate – 55 min/d 5 days/wk - ↓ Tumor weight in the active animals;
[2] old) (MC4-L2) Sed - ↓ Tumor volume in the active animals.
Subcutaneously
inoculated

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 Review Thieme

ercise performed was forced or voluntary. In incidence (34.8 % vs.

26.9 %) and multiplicity (87.0 % vs. 73.1 %), motorized-wheel exer-

Ki67. Apoptosis family: Apaf-1, apoptotic peptidase activating factor-1; BAX, BCL-2-associated X protein; CASP 3, caspase 3 and XIAP, X-linked inhibitor of apoptosis. Angiogenesis family: CD31, cluster; VEGF,
treadmill; FW, Free-wheel; MW, motorized-wheel. Wks, weeks; wk, week; min, minutes; d, day. Proliferation family: E2F-1, transcription factor; p27 and p27kip1, cyclin kinases inhibitors family members and
cises appeared to be more advantageous than free-wheel or tread-

Abbreviations: DMBA, 7,12-Dimethylbenz(a)anthracene; MNU, 1-methyl-1-nitrosoureia. BC, breast cancer; i.p., intraperitoneal; g.i., gastric intubation. Ex, active animals; Sed, sedentary animals. TRDM,
- ↑ Vessels density in the active animals; mill exercise (34.8 % vs. 9.5 % and 87.0 vs. 27.5 %, respectively). In

- ↓ Tumor volume in the active animals;

- ↑ Tumor volume in the active animals.
- ↑ Tumor weight in the active animals;
- ↓ Multiplicity in the active animals;
terms of tumor weight, running in a free wheel (79.4 %) was more

- ↓ Incidence in the active animals;

Tumor outcomes

beneficial than motorized-wheel (48.5 %) or treadmill (44.6 %) ex-

- ↓ VEGF and CD31 in the active

- ↑VEGF in the active animals.

- ↓ Ki67 in the active animals.

ercise. Tumor volume was significantly decreased with treadmill
exercise (70.7 %) compared with free-wheel exercise (33.8 %). No
research has been conducted about tumor volume under motor-
ized-wheel conditions.
Exercise performed on a motorized wheel favored an antiangi-
animals; ogenic environment (85 %), and the positive effects highlighted in
proliferation and apoptosis were not influenced by the modality of
the exercise performed. Moreover, no studies have been conduct-
ed to assess markers of apoptosis with forced exercise.
Frequency

5 days/wk
5 days/wk

5 days/wk

Intensity
Tumor burden appears to accumulate benefits from all levels of in-
tensity of training but to differing degrees. Increased benefits to

Downloaded by: York University libraries. Copyrighted material.

incidence (39.8 %) and multiplicity (88.1 %) were associated with
16/18 min/d
Duration

60 min/d

60 min/d

vigorous exercise training, and moderate-intensity exercise exert-

ed a stronger influence on tumor weight (50.7 %). Reductions in
tumor volume were higher for low-intensity exercise (84.7 %).
Positive and large effects were found between moderate-inten-
of all the publication used with the moderator variables considered for analysis and the main tumor outcomes.

Distance

sity exercise and tumor proliferation (88.6 %); apoptosis (85.6 %)

covered

and angiogenesis (80.7 %) exhibited better results with low-inten-

sity exercise. No studies have thoroughly examined proliferation
Exercise design

and angiogenesis markers under vigorous exercise conditions.

Moderate
Moderate
Intensity

Distance covered
Low

The proliferation and apoptosis outcomes were not moderated by

the distance the animals covered. Covering long distances appears
TRDM
TRDM

TRDM
Type

to confer moderate benefits in cancer incidence (35.8 %), tumor

volume (46.1 %) and angiogenesis (45.3 %); the effects were more
pronounced for tumor multiplicity (85.0 %) and tumor weight
duration

(68.5 %). Additionally, covering short distances also significantly

Study

35 wks

35 wks

affected tumor multiplicity (89.0 %), tumor weight (53.1 %) and

5 wks

tumor volume (79.2 %).

Duration
10 Ex + 11

10 Ex + 11

8 Ex + 8

The positive benefits found in tumor microenvironment markers

n

vascular endothelial growth factor. ↑ Increase, ↓ decrease.

Sed
Sed

Sed

of proliferation and apoptosis were not moderated by the duration

of exercise bouts.
Performing exercise for 30–45 min has a small positive influence
Animal/BC model

Sprague-Dawley rats

Sprague-Dawley rats
MNU (50 mg/Kg) i.p.

MNU (50 mg/Kg) i.p.

(MC4-L2 human BC)

BALB/c mice (42/48

on tumor incidence (15.9 %) and multiplicity (27.6 %) and a large

positive influence on tumor weight (55.3 %) and tumor volume
Cell inoculation
(50 days old)

(50 days old)

(69.0 %). In addition, short bouts of exercise confer large benefits

days old)

on tumor volume (98.7 %) and angiogenesis (80.7 %). Surprisingly,

being active for more than 45 min appears to be unfavorable in
terms of tumor incidence (17.8 %), tumor weight (37.1 %) and an-
giogenesis (75.5 %).
Faustino-Rocha et al
Continued.

Study [Reference]

Isanejad et al 2016
et al, 2016 [15]
Faustino-Rocha

Frequency
(1), 2016 [14]
▶Table 2 List

Exercise performed weekly is meaningfully correlated with inci-

dence, multiplicity, tumor volume and angiogenesis. However,
[31]

weekly exercise does not moderate the exercise-tumor weight re-

lationship or any of the other biomarkers families that were stud-

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
 ▶Table 3 Moderators of the relationship between exercise and tumor outcomes.

Incidence Multiplicity Weight Volume Proliferation Angiogenesis Apoptosis

Moderator k r p k r p k r p k r p k r p k r p k r p
Exercise Trdm 19 -0.095 0.032 5  − 0.275 0.002 9  − 0.446 0.000 9  − 0.695 0.000 1 4 0.045 0.644 0
type Fw 7  − 0.269 0.000 8  − 0.731 0.000 2  − 0.794 0.000 6  − 0.338 0.000 0 a) 3  − 0.204 0.110 10 a)
Mw 11  − 0.348 0.000 7  − 0.870 0.000 3  − 0.485 0.000 0 - - 9 1  − 0.850 0.000 2
Exercise Low 9  − 0.191 0.001 3  − 0.715 0.000 1  − 0.345 0.004 2  − 0.847 0.000 5  − 0.746 0.000 2  − 0.807 0.000 5  − 0.856 0.000
intensity Mod 13  − 0.107 0.052 4  − 0.764 0.000 9  − 0.507 0.000 6  − 0.685 0.000 5  − 0.886 0.000 3  − 0.354 0.001 5  − 0.776 0.000
Vig 6  − 0.398 0.000 5  − 0.881 0.000 1  − 0.378 0.001 1  − 0.202 0.342 0 - - 0 - - 2  − 0.747 0.000
Distance Sd 8  − 0.215 0.001 2  − 0.890 0.000 3  − 0.531 0.000 2  − 0.792 0.000 0 0 - - 0
a) a)
covered Ld 15  − 0.358 0.000 9  − 0.850 0.000 5  − 0.685 0.000 4  − 0.461 0.000 9 4  − 0.453 0.000 2
Exercise Sh 3  − 0.076 0.438 0 - - 0 - - 1  − 0.987 0.000 5 2  − 0.807 0.000 0
duration Med 13  − 0.159 0.003 3  − 0.276 0.015 6  − 0.553 0.000 6  − 0.690 0.000 5 0 - - 0
a) b)
L 3 0.178 0.280 2  − 0.273 0.049 2 0.371 0.008 3  − 0.078 0.450 0 2 0.755 0.000 0
Vl 1 0.166 0.423 0 - - 1  − 0.053 0.691 0 - - 0 0 0
Exercise 5d 16  − 0.133 0.004 4  − 0.235 0.019 4 7  − 0.720 0.000 0 4 0.054 0.644 0
frequency 6d 0 - - 6  − 0.847 0.000 0 a) 3  − 0.434 0.000 0 a) 0 - - 0 a)
7d 21  − 0.268 0.000 10  − 0.789 0.000 7 5  − 0.269 0.000 9 12

NOTE: Exercise intensity, distance covered, duration and exercise frequency as moderators of tumor incidence, multiplicity, weight, volume, proliferation, angiogenesis and apoptosis.

Number of cases (k) for correlation (r), and respective p-value.

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
a) Is not moderated by this exercise condition. b) Was not observed.

Trdm, treadmill; Fw, free-wheel; Mw, motorized-wheel; Mod, moderate; Vig, vigorous; Sd, short distance; Ld, long distance; Sh, Short; Med, medium; L, long; Vl, very long; d, days.

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Review Thieme

a
Study name Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value
Cohen, Chol and Wang, 1988 – 0.197 – 0.455 0.091 – 1.346 0.178
Cohen, Kendall Meschter et al, 1993 a – 0.428 – 0.840 0.297 – 1.174 0.240
Cohen, Kendall Meschter et al, 1993 b – 0.140 – 0.478 0.234 – 0.730 0.465
Colbert, Westerlind, Hursting et al, 2009 a 0.586 0.009 0.870 1.988 0.047
Colbert, Westerlind, Hursting et al, 2009 b 0.297 – 0.301 0.727 0.973 0.330
Colbert, Westerlind, Hursting et al, 2009 c 0.496 – 0.178 0.853 1.472 0.141
Faustino-Rocha et al, 2016 (1) – 0.143 – 0.547 0.316 – 0.598 0.550
Gillette, Zhu, Thompson et al, 1997 a 0.069 – 0.241 0.366 0.432 0.666
Gillette, Zhu, Thompson et al, 1997 b 0.480 0.135 0.722 2.644 0.008
Jiang, Zhu and Thompson, 2009 – 0.502 – 0.787 – 0.040 – 2.113 0.035
Jiang, Zhu and Thompson, 2013 – 0.566 – 0.835 – 0.081 – 2.242 0.025
Lane, Teer, Strahan et al, 1991 a – 0.176 – 0.464 0.145 – 1.079 0.281
Lane, Teer, Strahan et al, 1991 b – 0.253 – 0.508 0.042 – 1.687 0.092
Lane, Teer, Strahan et al, 1991 c – 0.022 – 0.283 0.242 – 0.162 0.871
Malicka et al, 2015 a 0.036 – 0.388 0.448 0.160 0.873
Malicka et al, 2015 b – 0.258 – 0.606 0.173 – 1.177 0.239
Malicka et al, 2015 c – 0.217 – 0.598 0.244 – 0.922 0.357
Mann, Jiang, Thompson et al, 2010 a – 0.523 – 0.738 – 0.210 – 3.098 0.002
Mann, Jiang, Thompson et al, 2010 b – 0.479 – 0.718 – 0.140 – 2.687 0.007
Moore and Tittle, 1973 – 0.664 – 0.892 – 0.170 – 2.495 0.013
Thompson, Ronan, Meeker et al, 1988 0.611 0.071 0.874 2.179 0.029
Thompson, Westerlind Singh et al, 1995 a – 0.077 – 0.346 0.204 – 0.534 0.594
Thompson, Westerlind Singh et al, 1995 b – 0.132 – 0.393 0.150 – 0.917 0.359

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Thompson, Westerlind Singh et al, 1995 c – 0.229 – 0.478 0.053 – 1.595 0.111
Thompson, Westerlind Singh et al, 1995 d – 0.204 – 0.457 0.079 – 1.420 0.155
Thompson, Westerlind Snedden et al, 1995 (1) a – 0.487 – 0.727 – 0.140 – 2.669 0.008
Thompson, Westerlind Snedden et al, 1995 (1) b – 0.501 – 0.734 – 0.162 – 2.791 0.005
Thompson, Westerlind Snedden et al, 1995 (1) c – 0.407 – 0.656 – 0.077 – 2.384 0.017
Thompson, Wolfe, Mctiernan et al, 2010 a – 0.427 – 0.632 – 0.165 – 3.088 0.002
Thompson, Wolfe, Mctiernan et al, 2010 b – 0.306 – 0.505 – 0.077 – 2.595 0.009
Westerlind, McCarty, Strange et al, 2003 – 0.160 – 0.497 0.220 – 0.820 0.412
Woods, Davis, Pate et al, 1994 a 0.266 – 0.192 0.629 1.143 0.253
Woods, Davis, Pate et al, 1994 b 0.166 – 0.238 0.522 0.801 0.423
Zhu, Jiang, Thompson et al, 2009 – 0.451 – 0.712 – 0.080 – 2.347 0.019
Zhu, Jiang, Thompson et al, 2008 – 0.525 – 0.794 – 0.084 – 2.292 0.022
Zhu, Jiang, Thompson et al, 2012 a – 0.530 – 0.807 – 0.061 – 2.187 0.029
Zhu, Jiang, Thompson et al, 2012 b – 0.499 – 0.798 – 0.003 – 1.973 0.049
– 0.202 – 0.295 – 0.106 – 4.084 0.000
– 1.00 – 0.50 0.00 0.50 1.00
b
Study name Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

Cohen, Kendall, Meschter et al, 1993 a – 0.389 – 0.574 – 0.166 – 3.307 0.001

Cohen, Kendall, Meschter et al, 1993 b – 0.195 – 0.420 0.053 – 1.545 0.122

Colbert, Westerlind, Hursting et al, 2009 0.301 0.012 0.544 2.037 0.042

Faustino-Rocha et al, 2016 – 0.087 – 0.473 0.327 – 0.400 0.689

Goh, Tsai, Bammier et al, 2013 – 0.600 – 0.804 – 0.269 – 3.251 0.001

Jiang, Zhu and Thompson, 2009 – 0.845 – 0.886 – 0.791 – 14.662 0.000

Jiang, Zhu and Thompson, 2013 – 0.881 – 0.909 – 0.845 – 19.310 0.000

Malicka et al, 2015 a – 0.154 – 0.491 0.223 – 0.794 0.427

Malicka et al, 2015 b – 0.355 – 0.640 0.016 – 1.880 0.060

Malicka et al, 2015 c – 0.322 – 0.635 0.083 – 1.570 0.116

Mann, Jiang, Thompson et al, 2010 a – 0.899 – 0.928 – 0.861 – 16.698 0.000

Mann, Jiang, Thompson et al, 2010 b – 0.825 – 0.876 – 0.756 – 12.347 0.000

Murphy, Davis, Barrileaux et al, 2011 – 0.400 – 0.660 – 0.055 – 2.254 0.024

Steiner, Davis, Murphy et al, 2013 0.342 – 0.009 0.619 1.910 0.056

Thompson, Wolfe, Mctiernan et al, 2010 a – 0.953 – 0.966 – 0.936 – 22.182 0.000

Thompson, Wolfe, Mctiernan et al, 2010 b – 0.902 – 0.928 – 0.867 – 18.056 0.000

Zhu, Jiang, Thompson et al, 2009 – 0.916 – 0.943 – 0.877 – 15.092 0.000

Zhu, Jiang, Thompson et al, 2008 – 0.868 – 0.901 – 0.825 – 17.099 0.000

Zhu, Jiang, Thompson et al, 2012 a – 0.505 – 0.660 – 0.309 – 4.611 0.000

Zhu, Jiang, Thompson et al, 2012 b – 0.442 – 0.614 – 0.231 – 3.875 0.000
– 0.632 – 0.766 – 0.446 – 5.514 0.000

– 1.00 – 0.50 0.00 0.50 1.00

▶Fig. 2 a Forest plot of the meta-analysis depicting the influence of exercise on tumor incidence. Correlation: effect size (r) for each study. CI = con-
fidence interval. a, b, c, d: different measures in different exercise protocols within the same study. b: Forest plot of the meta-analysis depicting the
influence of exercise on tumor multiplicity. Correlation: effect size (r) for each study. CI = confidence interval. a, b: different measures in different
exercise protocols within the same study.

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
 c
Study name Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

Aveseh et al, 2015 – 0.233 – 0.585 0.192 – 1.078 0.281

Faustino-Rocha et al, 2016 a 0.543 0.210 0.763 3.019 0.003
Faustino-Rocha et al, 2016 b 0.135 – 0.282 0.509 0.625 0.532
Jiang, Zhu and Thompson, 2013 – 0.581 – 0.679 – 0.462 – 7.967 0.000
Steiner, Davis Murphy et al, 2013 – 0.404 – 0.658 – 0.067 – 2.322 0.020
Westerlind, McCarty, Strange et al, 2003 b – 0.705 – 0.782 – 0.607 – 9.962 0.000
Westerlind, McCarty, Strange et al, 2003 c – 0.271 – 0.519 0.019 – 1.835 0.066
Westerlind, McCarty, Strange et al, 2003 d – 0.763 – 0.827 – 0.679 – 11.227 0.000
Westerlind, McCarty, Strange et al, 2003 a – 0.254 – 0.463 – 0.019 – 2.113 0.035
Woods, Davis, Pate et al, 1994 b – 0.053 – 0.302 0.204 – 0.397 0.691
Woods, Davis, Pate et al, 1994 a – 0.078 – 0.318 0.170 – 0.615 0.539
Zhu, Jiang, Thompson et al, 2008 – 0.834 – 0.876 – 0.781 – 15.179 0.000
Zhu, Jiang, Thompson et al, 2012 a – 0.378 – 0.566 – 0.152 – 3.193 0.001
Zhu, Jiang, Thompson et al, 2012 b – 0.345 – 0.540 – 0.113 – 2.870 0.004

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– 0.366 – 0.557 – 0.139 – 3.083 0.002

– 1.00 – 0.50 0.00 0.50 1.00

d
Study name Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

Aveseh et al, 2015 – 0.233 – 0.585 0.192 – 1.078 0.281

Cohen, Choi and Wang, 1988 – 0.130 – 0.355 0.109 – 1.070 0.284
Colbert, Westerlind, Hursting et al, 2009 – 0.254 – 0.509 0.041 – 1.694 0.090
Faustino-Rocha et al, 2016 0.540 0.197 0.765 2.924 0.003
Goh, Tsai, Bammier et al, 2013 a – 0.570 – 0.791 – 0.216 – 2.967 0.003
Goh Tsai, Bammier et al, 2013 b – 0.499 – 0.727 – 0.172 – 2.867 0.004
Isanejad et al, 2016 – 0.987 – 0.994 – 0.974 – 14.049 0.000
Malicka et al, 2015 a 0.233 – 0.141 0.549 1.226 0.220
Malicka et al, 2015 b – 0.155 – 0.504 0.237 – 0.771 0.441
Malicka et al, 2015 c – 0.202 – 0.557 0.215 – 0.949 0.342
Murphy, Davis Barrilleaux et al, 2011 – 0.359 – 0.634 – 0.004 – 1.980 0.048
Steiner, Davis, Murphy et al, 2013 – 0.371 – 0.637 – 0.025 – 2.095 0.036
Welsch M., Cohen and Welsch C., 1995 – 0.437 – 0.631 – 0.192 – 3.346 0.001
Westerlind, McCarty, Strange et al, 2003 a – 0.834 – 0.868 – 0.792 – 18.879 0.000
Westerlind, McCarty, Strange et al, 2003 b – 0.629 – 0.719 – 0.518 – 8.701 0.000
– 0.443 – 0.668 – 0.143 – 2.812 0.005
– 1.00 – 0.50 0.00 0.50 1.00

▶Fig. 2 Continued. c: Forest plot of the meta-analysis depicting the influence of exercise on tumor weight. Correlation: effect size (r) for each
study. CI = confidence interval. a, b, c, d: different measures in different exercise protocols within the same study. d: Forest plot of the meta-analysis
depicting the influence of exercise on tumor volume. Correlation: effect size (r) for each study. CI = confidence interval. a, b: different measures in
different exercise protocols within the same study.

ied. Tumor incidence (26.8 %), multiplicity (84.7 %) and angiogen-
esis (45.3 %) benefit from higher frequencies of exercise. However,
exercising five days per week appears to be sufficient for conferring
benefits to tumor volume (72 %).
After observing funnel plots and considering Egger’s regression
and Begg’s rank correlation, we verified the absence of study bias
in tumor incidence (p = 0.41712), multiplicity (p = 0.00569), tumor
weight (p = 0.01240), tumor volume (p = 0.14913), angiogenesis
(p = 0.50000) and apoptosis (p = 0.27426). However, bias was found
in proliferation (p = 0.00037).
Discussion
The impact of exercise was observed in the reduction of the total
number of tumors in the active animals (20.2 %). We also noted a
reduction in the number of tumors per animal (63.2 %), a decrease
in tumor weight (36.6 %) and a decrease in tumor volume (44.3 %).

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
Review Thieme

a
Study name Biomarkers Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

Isanejad et al, 2016 ki67 – 0.864 – 0.935 – 0.726 – 6.608 0.000

Jiang, Zhu and Thompson, 2009 a CYCLIN D1 – 0.876 – 0.944 – 0.738 – 6.472 0.000
Jiang, Zhu and Thompson, 2009 a E2F-1 – 0.543 – 0.798 – 0.124 – 2.466 0.014
Jiang, Zhu and Thompson, 2009 b p27kip1 – 0.468 – 0.762 – 0.013 – 2.013 0.044
Jiang, Zhu and Thompson, 2009 c p27kip1 – 0.596 – 0.822 – 0.209 – 2.838 0.005
Jiang, Zhu and Thompson, 2013 CYCLIN D1 – 0.948 – 0.968 – 0.914 – 13.780 0.000
Jiang, Zhu and Thompson, 2013 p27 – 0.882 – 0.929 – 0.805 – 10.010 0.000
Zhu, Jiang, Thompson et al, 2009 CYCLIN D1 – 0.787 – 0.905 – 0.556 – 4.783 0.000
Zhu, Jiang, Thompson et al, 2009 E2F-1 – 0.881 – 0.946 – 0.749 – 6.603 0.000
Zhu, Jiang, Thompson et al, 2009 p27kip1 – 0.393 – 0.725 – 0.087 – 1.620 0.105
– 0.794 – 0.881 – 0.655 – 7.132 0.000
– 1.00 – 0.50 0.00 0.50 1.00

b
Study name Biomarkers Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

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Zhu, Jiang, Thompson et al, 2009 Apaf-1 – 0.773 – 0.899 – 0.529 – 4.589 0.000
Zhu, Jiang, Thompson et al, 2009 BAX – 0.384 – 0.710 0.124 – 1.477 0.140
Zhu, Jiang, Thompson et al, 2009 BCL-2 – 0.752 – 0.890 – 0.438 – 4.316 0.000
Zhu, Jiang, Thompson et al, 2009 CASP 3 – 0.946 – 0.975 – 0.836 – 9.030 0.000
Zhu, Jiang, Thompson et al, 2009 XIAP – 0.474 – 0.765 – 0.022 – 2.046 0.041
Jiang, Zhu and Thompson, 2009 Apaf-1 – 0.685 – 0.861 – 0.362 – 3.582 0.000
Jiang, Zhu and Thompson, 2009 BAX – 0.862 – 0.937 – 0.710 – 6.144 0.000
Jiang, Zhu and Thompson, 2009 BCL-2 – 0.904 – 0.958 – 0.797 – 7.270 0.000
Jiang, Zhu and Thompson, 2009 CASP 3 – 0.795 – 0.879 – 0.663 – 7.423 0.000
Jiang, Zhu and Thompson, 2009 XIAP – 0.939 – 0.972 – 0.872 – 8.677 0.000
Jiang, Zhu and Thompson, 2013 BAX – 0.850 – 0.911 – 0.753 – 8.895 0.000
Jiang, Zhu and Thompson, 2013 BCL-2 – 0.516 – 0.713 – 0.244 – 3.471 0.001
– 0.798 – 0.872 – 0.690 – 3.726 0.000
– 1.00 – 0.50 0.00 0.50 1.00

c
Study name Biomarkers Statistics for each study Correlation and 95 % CI
Lower Upper
Correlation limit limit Z-Value p-Value

Faustino-Rocha et al, 2016 a PER VESS 0.833 0.692 0.913 6.793 0.000
Faustino-Rocha et al, 2016 b VEGF 0.616 0.322 0.802 3.657 0.000
Isanejad et al, 2016 a VEGF – 0.703 – 0.861 – 0.420 – 4.025 0.000
Isanejad et al, 2016 b CD31 – 0.867 – 0.936 – 0.732 – 6.686 0.000
Jones, Viglianti, Tashjian et al, 2010 CD31 – 0.102 – 0.501 0.333 – 0.448 – 0.654
Jones, Viglianti, Tashjian et al, 2010 PER VESS – 0.477 – 0.737 – 0.096 – 2.406 0.016
Jones, Viglianti, Tashjian et al, 2010 VEGF 0.041 – 0.387 0.455 0.179 0.858

Zhu, Jiang, Thompson et al, 2009 VEGF – 0.850 – 0.932 – 0.684 – 5.877 0.000
– 0.258 – 0.734 0.392 – 0.759 0.448
– 1.00 – 0.50 0.00 0.50 1.00

▶Fig. 3 a: Forest plot of the meta-analysis depicting the influence of exercise on biomarkers of proliferation. Correlation: effect size (r) for each
study in proliferation. CI = confidence interval. a, b, c: different measures within the same study. Abbreviations: E2F-1, transcription factor; p27 and
p27kip1, cyclin kinases inhibitors family members and Ki67. b: Forest plot of the meta-analysis depicting the influence of exercise on biomarkers of
apoptosis. Correlation: effect size (r) for each study in. CI = confidence interval. Abbreviations: Apaf-1, apoptotic peptidase activating factor-1; BAX,
BCL-2-associated X protein; CASP 3, caspase 3; XIAP, X-linked inhibitor of apoptosis. c: Forest plot of the meta-analysis depicting the influence of
exercise on biomarkers of angiogenesis. Correlation: effect size (r) for each study in. CI = confidence interval. Abbreviations: CD31, cluster; PER VESS,
number of perfused vessels; VEGF, vascular endothelial growth factor.

Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
 In contrast to some preclinical research linking an increased
tumor burden to exercise [7, 9, 14, 21, 46, 60, 66, 73], these data
provide a step forward by quantifying the benefits highlighted in
the majority of previous preclinical data [2, 7–9, 14, 23, 31, 33, 34,
42, 46, 47, 51, 53, 60, 67–70, 72, 73, 75–77]. Tumor incidence was
the only variable associated with small benefits, which can be part-
ly related to the breast cancer models used. The negative results
found in this variable were reported in five studies [9, 21, 46,
66, 73]. Each of them used a different tumor model that may have
resulted in differences in tumor phenotypes and consequently in
different behaviors when exposed to exercise [22, 27, 37]. Howev-
er, no data were available regarding the different histological types
of the developed tumors, and so we cannot know for sure whether
this could be the case. Yet, three of the five studies that have re-
ported negative results in tumor incidence, also reported a benefi-
cial effect of exercise in tumor burden, namely, in tumor weight
[73] and in tumor volume [9, 46]. Additionally, the characteristics
of exercise protocols and the total duration of the experiments can
also be a factor that might explain this negative data. Indeed, the
negative data reported for tumor incidence in one of the experi-
ments, only occurred in animals that were exposed to exercise of
low intensity [46]. Nevertheless, several reports have noted a re-
duction of malignant and invasive types of tumor in active rodents
compared with sedentary ones [14, 15]. Our results confirm the
evidence of a strong association between exercise and cancer out-
comes in human patients [3, 29, 59, 61].
Exercise improved the deregulation of tumor proliferation
(79.4 %) and apoptosis (79.8 %). Furthermore, there is some evi-
dence, albeit inconsistent, for positive effects in tumor angiogen-
esis (25.6 %), which is consistent with some previous research [33,
34, 49, 53, 54, 64, 65, 71, 75, 77]. Nevertheless, only a few preclin-
ical studies have examined changes in tumor biology regarding
proliferation [33, 34, 75], angiogenesis [15, 31, 39, 75] and apop-
tosis [33, 34, 75]. Moreover, experimental protocols with voluntary
exercise were the most often used; considering the intermittent
features of voluntary exercise in animals, this situation is a clear
limitation to speculating about similar results in a clinical context.
It is clear that increased proliferation is a hallmark of malignant
tumors and a key feature of tumor progression that is associated
with a higher risk of recurrence and a shorter survival duration [62].
Additionally, suppression of apoptosis is believed to play a central
role in the development and progression of breast cancer
[5, 12, 13]. The present data strongly support the recommenda-
tion for exercise in order to modulate the proliferative and the ap-
optotic rate in a tumor environment.
The present results do not allow us to confirm a consistent rela-
tion between exercise and angiogenesis. However, in spite of the
undoubtedly important role that angiogenesis plays in the growth,
progression and metastasis of a tumor [45, 54], recent research has
shown that the process of tumor angiogenesis is far from clearly
understood [32]. In fact, it seems that the antiangiogenic therapy
more than reduced tumor vessels, normalized tumor vasculature
reducing tumor vessel permeability and as a result may improve
chemotherapeutic delivery (window of opportunity) [44]. Could
exercise create a window of opportunity for establishing optimal
conditions for chemical therapy? This might explain some of the
results in the studies used in this review in which the active animals
Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
showed high levels of VEGF (vascular endothelial growth factor) ex-
pression but, at the same time, developed tumors histologically
less aggressive [15].
Another finding of this review is that the diversity of exercise
protocols used in the selected studies might be an obstacle to cre-
ating an accurate definition of the type and amount of exercise nec-
essary to induce better tumor outcomes.
Voluntary exercise appears to exert more influence on the inci-
dence, multiplicity and weight of tumors than forced exercise.
However, forced exercise exhibited better tumor volume results.
Favorable influences were also confirmed in multiplicity and tumor
weight under forced-exercise conditions. Nevertheless, it is worth
noting that even though voluntary exercise more strongly influ-
enced tumor outcomes, this situation persisted in motorized-wheel
exercise, which appears to be an argument in favor of protocols
that can manipulate exercise intensity. Forced exercise also proved
to be effective at inhibiting tumors [53, 67, 68, 72], and it may be
worthwhile to gathering information about exercise prescriptions
in a clinical context.
Downloaded by: York University libraries. Copyrighted material.
Moderate- or vigorous-intensity exercise favorably affected all
the variables that we considered. For tumor volume, angiogenesis
and proliferation, the benefits were even more pronounced for low-
intensity exercise. Similar results can be found in the previously
published literature: a reduction in cancer recurrence and survival
are associated with moderate and vigorous exercise. However, in
general, the results of the majority of the studies, mostly meta-
analyses, failed to present significant results about the ideal
amount of exercise (i. e., intensity, duration and frequency) to
achieve benefits. The vast majority of cases used studies that poor-
ly reported the amount of exercise performed or only reported lev-
els of physical activity estimated by self-response [17, 19, 26, 29,
48, 59].
Interestingly, in this study we found benefits associated with
low-intensity exercise, a level of intensity that is not usually asso-
ciated with large effects and is therefore not usually recommend-
ed in international guidelines [41]. Again, this may be due to the
small number of studies that evaluated the microenvironment of
the tumor. Nevertheless, intensity appears to be a determining fac-
tor in modulating tumor outcomes [8, 9, 46, 67, 68, 73, 77]. There
should accordingly be a preference for study designs in which the
intensity can be controlled. Such studies are most likely to yield im-
portant information that advances this field of research [1].
In contrast to some preclinical results [23, 70], the distances
covered during exercise do not appear to affect tumor outcomes.
In fact, based on the present results, it appears that intensity in-
stead of distance may have more of an influence on tumor out-
comes.
Tumor burden accrues more benefits when exercise is per-
formed for 30–45 min. Only tumor volume and angiogenesis [31]
benefitted from short periods of exercise. Unexpectedly, bouts of
exercise longer than 45 min adversely impacted tumor incidence,
tumor weight and angiogenesis [14, 15, 73].
Higher exercise frequencies (6 or 7 days per week) are correlat-
ed with better tumor outcomes in incidence, multiplicity and an-
giogenesis; for tumor volume, running 5 days per week is preferred
[7–9, 23, 33, 34, 39, 47, 51, 53, 60, 69, 70, 73, 75–77].
 Review
Curiously, the benefits highlighted by these quantitative prolif-
eration and apoptosis data do not appear to be influenced by any
of the moderating variables, with the exception of intensity. This
finding may be related to the limited number of studies that used
forced exercise protocols to examine the tumor microenvironment
[14, 15, 31]. However, a key question still remains: does only inten-
sity matter?
The present results highlight the importance of new research
that makes use of mechanisms to assess the intensity, frequency
and duration of performed exercise. It will then be possible to test
the amount of exercise necessary to improve either, tumor out-
comes or an aggressive intratumoral environment.
Given the diversity of exercise protocols used in the studies in-
cluded in this review, accompanied by the fact that only a minority
of studies clearly defined the exercise model in humans that they
wished to reproduce, it is impossible to extrapolate specific and ac-
curate recommendations to a clinical context.
In general, additional research is necessary that takes into ac-
count a methodological approach mimicking the exercises that can
be performed by humans with breast cancer. Understanding the
effects of specific (intensity, duration and frequency) exercise pre-
scriptions on physiological outcomes across different stages of can-
cer will allow researchers to personalize exercise prescriptions.
Study limitations
There are several limitations to this study. First, there was signifi-
cant heterogeneity among the studies that we attempted to meas-
ure performing a sensitivity analysis and analyzing exercise-related
moderators. Furthermore, publication bias was found in one of the
variables studied (i. e., proliferation). However, after performing
the sensitivity analysis we verified that the overall effect had a small
variation (3.3 % vs. 2.5 %) in this variable.
Finally, studies published in languages other than English were
not considered. Although the exclusion of non-English-language
studies might have resulted in smaller intervention effects, the lan-
guage bias is generally small [40].
Conclusions
To the best of our knowledge, this meta-analysis is the first attempt
to quantify the results of preclinical research addressing the exer-
cise-breast cancer relationship. Our primary findings were: 1) there
is convincing evidence from the preclinical data that exercise is as-
sociated with tumor burden reduction; 2) there is evidence sug-
gesting that exercise may result in beneficial changes in the levels
of proliferation and apoptotic biomarkers in the tumoral microen-
vironment; and 3) there is insufficient evidence regarding the as-
sociation between exercise and a positive modulation of the angi-
ogenic events in the tumoral environment.
Finally, there is evidence that the intensity, duration and fre-
quency of exercise are important determinants of tumor outcomes.
Nevertheless, uniform preclinical exercise designs are necessary to
facilitate comparisons of results from different studies, and define
the amounts of exercise required to alter carcinogenesis.
Future research directions include the need for more preclinical
studies, particularly in tumor biology, and for exercise conditions that
make it possible to manipulate the amount of exercise performed.
Figueira ACC et al. Exercise-induced Benefits in Breast Cancer Outcomes in Animals.  Int J Sports Med
Thieme
Acknowledgements
This study was funded by CIAFEL – Research Center in Physical
­Activity, Health and Leisure, Faculty of Sport, University of Porto,
Porto, Portugal.
Conflict of Interest
The authors declare that they have no conflict of interest.
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